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Subclone wars p.160

Pluripotent stem cells, which give rise to every cell type, can acquire cancer-causing genetic mutations when grown in vitro. This finding has implications for the use of pluripotent cells in basic research and in the clinic. See Letter p.229

Stephen Chanock

doi: 10.1038/nature22490

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Asian glaciers are a reliable water source p.161

The people, economies and agriculture of central Asia and parts of south Asia rely on water from mountains. Modelling suggests that glacier melt, in particular, is a key water source during dry periods in some of these regions. See Letter p.169

Tobias Bolch

doi: 10.1038/545161a

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An ion-transport enzyme that rocks p.162

Previous crystal structures of membrane-spanning enzymes called ATPases have revealed that the enzymes undergo complex movements. The movements, it now emerges, involve rocking in place in the membrane. See Article p.193

Kathleen J. Sweadner

doi: 10.1038/nature22492

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Atomic envoy enables molecular control p.164

A technique for manipulating molecules uses an intermediary atom to query a nearby molecule's energy state and produces 'quantum superpositions' of these states, a prerequisite for extremely high-precision spectroscopy. See Letter p.203

Wes Campbell

doi: 10.1038/545164a

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The long and short of a DNA-damage response p.165

Ultraviolet light can damage DNA, triggering a general shutdown of gene transcription — yet some genes are activated by UV light. An investigation of this counter-intuitive behaviour reveals a surprising gene-regulation mechanism.

Antonio Conconi & Brendan Bell

doi: 10.1038/nature22488

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A social spin on language analysis p.166

Understanding the prevalence and impact of personal attacks in online discussions is challenging. A method that combines crowdsourcing and machine learning provides a way forward, but caveats must be considered.

doi: 10.1038/545166a

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Articles

Whole-genome landscapes of major melanoma subtypes p.175

The first large, high-coverage whole-genome sequencing study of melanomas from cutaneous, acral and mucosal sites.

Nicholas K. Hayward, James S. Wilmott, Nicola Waddell, Peter A. Johansson, Matthew A. Field, Katia Nones, Ann-Marie Patch, Hojabr Kakavand, Ludmil B. Alexandrov, Hazel Burke + et al.

doi: 10.1038/nature22071

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Maintenance of persistent activity in a frontal thalamocortical loop p.181

Thalamic neurons show selective persistent activity that predicts movement direction, and their photoinhibition decreases activity in the anterior lateral motor cortex, and vice versa, suggesting that persistent activity requires reciprocal excitation in a thalamocortical loop.

Zengcai V. Guo, Hidehiko K. Inagaki, Kayvon Daie, Shaul Druckmann, Charles R. Gerfen & Karel Svoboda

doi: 10.1038/nature22324

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Visualization and targeting of LGR5+ human colon cancer stem cells p.187

LGR5+ cells in human colorectal cancer tissue xenografted into mice act as cancer stem cells, and differentiated cancer cells can revert to cancer stem cells and express LGR5 after ablation of existing LGR5+ cells.

Mariko Shimokawa, Yuki Ohta, Shingo Nishikori, Mami Matano, Ai Takano, Masayuki Fujii, Shoichi Date, Shinya Sugimoto, Takanori Kanai & Toshiro Sato

doi: 10.1038/nature22081

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Protein–phospholipid interplay revealed with crystals of a calcium pump p.193

Solvent contrast modulation reveals how the lipid bilayer actively participates in the conformational switches of Ca2+-ATPase through the actions of tryptophan, arginine and lysine residues, which function as membrane floats and anchors.

Yoshiyuki Norimatsu, Kazuya Hasegawa, Nobutaka Shimizu & Chikashi Toyoshima

doi: 10.1038/nature22357

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Letters

Multi-phase volcanic resurfacing at Loki Patera on Io p.199

Interferometric telescope observations of the Jovian moon Io reveal that the floor of the Loki Patera volcano has been resurfaced in two waves, with different starting times and velocities.

K. de Kleer, M. Skrutskie, J. Leisenring, A. G. Davies, A. Conrad, I. de Pater, A. Resnick, V. Bailey, D. Defrère, P. Hinz + et al.

doi: 10.1038/nature22339

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The effect of illumination on the formation of metal halide perovskite films p.208

Films of metal halide perovskite are used as the absorber material in solar cells, and light irradiation during their formation is shown to affect their crystallization, morphology and photovoltaic performance.

Amita Ummadisingu, Ludmilla Steier, Ji-Youn Seo, Taisuke Matsui, Antonio Abate, Wolfgang Tress & Michael Grätzel

doi: 10.1038/nature22072

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Decarboxylative alkenylation p.213

Starting with alkyl carboxylic acids, a simple olefin synthesis using any substitution pattern or geometry, based on amide-bond synthesis with nickel- or iron-based catalysis, is described.

Jacob T. Edwards, Rohan R. Merchant, Kyle S. McClymont, Kyle W. Knouse, Tian Qin, Lara R. Malins, Benjamin Vokits, Scott A. Shaw, Deng-Hui Bao, Fu-Liang Wei + et al.

doi: 10.1038/nature22307

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FGF-dependent metabolic control of vascular development p.224

Fibroblast growth factor receptor (FGFR) signalling is a crucial regulator of endothelial metabolism and vascular development.

Pengchun Yu, Kerstin Wilhelm, Alexandre Dubrac, Joe K. Tung, Tiago C. Alves, Jennifer S. Fang, Yi Xie, Jie Zhu, Zehua Chen, Frederik De Smet + et al.

doi: 10.1038/nature22322

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Human pluripotent stem cells recurrently acquire and expand dominant negative P53 mutations p.229

The authors surveyed whole-exome and RNA-sequencing data from 252 unique pluripotent stem cell lines, some of which are in the pipeline for clinical use, and found that approximately 5% of cell lines had acquired mutations in the TP53 gene that allow mutant cells to rapidly outcompete non-mutant cells, but do not prevent differentiation.

Florian T. Merkle, Sulagna Ghosh, Nolan Kamitaki, Jana Mitchell, Yishai Avior, Curtis Mello, Seva Kashin, Shila Mekhoubad, Dusko Ilic, Maura Charlton + et al.

doi: 10.1038/nature22312

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Surrogate Wnt agonists that phenocopy canonical Wnt and β-catenin signalling p.234

Wnt proteins modulate cell proliferation and differentiation and the self-renewal of stem cells by inducing β-catenin-dependent signalling through the Wnt receptor frizzled (FZD) and the co-receptors LRP5 and LRP6 to regulate cell fate decisions and the growth and repair of several tissues. The 19 mammalian Wnt proteins are cross-reactive with the 10 FZD receptors, and this has complicated the attribution of distinct biological functions to specific FZD and Wnt subtype interactions. Furthermore, Wnt proteins are modified post-translationally by palmitoylation, which is essential for their secretion, function and interaction with FZD receptors. As a result of their acylation, Wnt proteins are very hydrophobic and require detergents for purification, which presents major obstacles to the preparation and application of recombinant Wnt proteins. This hydrophobicity has hindered the determination of the molecular mechanisms of Wnt signalling activation and the functional importance of FZD subtypes, and the use of Wnt proteins as therapeutic agents. Here we develop surrogate Wnt agonists, water-soluble FZD–LRP5/LRP6 heterodimerizers, with FZD5/FZD8-specific and broadly FZD-reactive binding domains. Similar to WNT3A, these Wnt agonists elicit a characteristic β-catenin signalling response in a FZD-selective fashion, enhance the osteogenic lineage commitment of primary mouse and human mesenchymal stem cells, and support the growth of a broad range of primary human organoid cultures. In addition, the surrogates can be systemically expressed and exhibit Wnt activity in vivo in the mouse liver, regulating metabolic liver zonation and promoting hepatocyte proliferation, resulting in hepatomegaly. These surrogates demonstrate that canonical Wnt signalling can be activated by bi-specific ligands that induce receptor heterodimerization. Furthermore, these easily produced, non-lipidated Wnt surrogate agonists facilitate functional studies of Wnt signalling and the exploration of Wnt agonists for translational applications in regenerative medicine.

Claudia Y. Janda, Luke T. Dang, Changjiang You, Junlei Chang, Wim de Lau, Zhendong A. Zhong, Kelley S. Yan, Owen Marecic, Dirk Siepe, Xingnan Li + et al.

doi: 10.1038/nature22306

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Non-equivalence of Wnt and R-spondin ligands during Lgr5+ intestinal stem-cell self-renewal p.238

The canonical Wnt/β-catenin signalling pathway governs diverse developmental, homeostatic and pathological processes. Palmitoylated Wnt ligands engage cell-surface frizzled (FZD) receptors and LRP5 and LRP6 co-receptors, enabling β-catenin nuclear translocation and TCF/LEF-dependent gene transactivation. Mutations in Wnt downstream signalling components have revealed diverse functions thought to be carried out by Wnt ligands themselves. However, redundancy between the 19 mammalian Wnt proteins and 10 FZD receptors and Wnt hydrophobicity have made it difficult to attribute these functions directly to Wnt ligands. For example, individual mutations in Wnt ligands have not revealed homeostatic phenotypes in the intestinal epithelium—an archetypal canonical, Wnt pathway-dependent, rapidly self-renewing tissue, the regeneration of which is fueled by proliferative crypt Lgr5+ intestinal stem cells (ISCs). R-spondin ligands (RSPO1–RSPO4) engage distinct LGR4–LGR6, RNF43 and ZNRF3 receptor classes, markedly potentiate canonical Wnt/β-catenin signalling, and induce intestinal organoid growth in vitro and Lgr5+ ISCs in vivo. However, the interchangeability, functional cooperation and relative contributions of Wnt versus RSPO ligands to in vivo canonical Wnt signalling and ISC biology remain unknown. Here we identify the functional roles of Wnt and RSPO ligands in the intestinal crypt stem-cell niche. We show that the default fate of Lgr5+ ISCs is to differentiate, unless both RSPO and Wnt ligands are present. However, gain-of-function studies using RSPO ligands and a new non-lipidated Wnt analogue reveal that these ligands have qualitatively distinct, non-interchangeable roles in ISCs. Wnt proteins are unable to induce Lgr5+ ISC self-renewal, but instead confer a basal competency by maintaining RSPO receptor expression that enables RSPO ligands to actively drive and specify the extent of stem-cell expansion. This functionally non-equivalent yet cooperative interaction between Wnt and RSPO ligands establishes a molecular precedent for regulation of mammalian stem cells by distinct priming and self-renewal factors, with broad implications for precise control of tissue regeneration.

Kelley S. Yan, Claudia Y. Janda, Junlei Chang, Grace X. Y. Zheng, Kathryn A. Larkin, Vincent C. Luca, Luis A. Chia, Amanda T. Mah, Arnold Han, Jessica M. Terry + et al.

doi: 10.1038/nature22313

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Dominant protection from HLA-linked autoimmunity by antigen-specific regulatory T cells p.243

The molecular mechanism of Goodpasture disease is modelled to mechanistically determine how a human leukocyte antigen (HLA) allele can exert its dominant protective effect in autoimmune disease.

Joshua D. Ooi, Jan Petersen, Yu H. Tan, Megan Huynh, Zoe J. Willett, Sri H. Ramarathinam, Peter J. Eggenhuizen, Khai L. Loh, Katherine A. Watson, Poh Y. Gan + et al.

doi: 10.1038/nature22329

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